title: Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling.
abstract: Genes with common profiles of the presence and absence in disparate genomes tend to function in the same pathway. By mapping all human genes into about 1000 clusters of genes with similar patterns of conservation across eukaryotic phylogeny, we determined that sets of genes associated with particular diseases have similar phylogenetic profiles. By focusing on those human phylogenetic gene clusters that significantly overlap some of the thousands of human gene sets defined by their coexpression or annotation to pathways or other molecular attributes, we reveal the evolutionary map that connects molecular pathways and human diseases. The other genes in the phylogenetic clusters enriched for particular known disease genes or molecular pathways identify candidate genes for roles in those same disorders and pathways. Focusing on proteins coevolved with the microphthalmia-associated transcription factor (MITF), we identified the Notch pathway suppressor of hairless (RBP-Jk/SuH) transcription factor, and showed that RBP-Jk functions as an MITF cofactor.
authors.affiliation: 1] Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Tabach
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan
authors.forename: Abrahan
authors.initials: A
authors.lastname: Hernández-Hernández
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Messer
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fukuda
authors.forename: Anna
authors.initials: A
authors.lastname: Kouznetsova
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Liu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lilienthal
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
authors.forename: Gary
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005658:Fungi / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D016678:Genome; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051739:Microphthalmia-Associated Transcription Factor / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008850:Microphthalmos / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497570:RBPJ protein, human